The Role of Novel Anti-Inflammatory Drugs in the Repair of Ischemic-Injured Equine Jejunum

Abstract

Following colic surgery, ischemic-injured intestine may remain which must recover for the horse to survive. However, the commonly used analgesic, flunixin meglumine, a non selective cyclooxygenase (COX) inhibitor, may retard the repair of ischemic-injured jejunum. Therefore, we investigated alternative anti-inflammatory drugs which may allow recovery of ischemic-injured jejunum whilst providing effective analgesia. The effect of 0.9% saline 1ml/50kg, flunixin meglumine 1mg/kg IV every 12 hours, lidocaine 1.3mg/kg loading dose and 0.05mg/kg/minute constant rate infusion IV, or the two drugs combined, was evaluated on recovery of mucosal barrier function in equine jejunum following 2 hours of ischemia and 18 hours of recovery (n=6 horses/group). Flunixin meglumine inhibited the recovery of mucosal barrier function as evidenced by a lower transepithelial resistance (TER) and increased LPS flux across ischemic-injured mucosa from horses in that treatment group. When treatment with flunixin meglumine was combined with lidocaine, recovery of mucosal barrier function was not retarded. The mucosal influx of neutrophils seen with flunixin meglumine treatment was ameliorated by treatment with lidocaine. Lidocaine inhibited upregulation of COX-2 in ischemic-injured jejunum. The same model was used to evaluate the effect of a COX-2 preferential inhibitor, firocoxib at 0.09mg/kg IV. Pain scores did not increase after surgery in horses treated with flunixin meglumine or firocoxib. Unlike flunixin meglumine, firocoxib allowed recovery of TER and did not increase LPS flux across ischemic-injured jejunum. Analyses of plasma prostanoids suggested that firocoxib is COX-2 selective in horses. The effect of lidocaine on neutrophils was evaluated by incubating isolated equine neutrophils with 0.1-1000ï ­g/ml of lidocaine in vitro. Neutrophil adhesion and migration in response to stimulants was subsequently evaluated. LTB4 and IL-8 induced adhesion were increased at 1mg/ml of lidocaine. Migration increased with increasing concentration of lidocaine, in response to the same stimulants. Therefore, the use of firocoxib, or lidocaine in combination with flunixin meglumine, may be advantageous for horses recovering from ischemic intestinal injury, compared to treatment with a non-selective COX inhibitor, such as flunixin meglumine, alone.